Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Abstract

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

Deubiquitination of CD36 by UCHL1 promotes foam cell formation

“…To further explore the molecular mechanism of UCHL1 on the regulation of CD36, we observed the inhibition of UCHL1 promotes CD36 degradation. Previous study has demonstrated that CD36 degradation involved in ubiquitin system 20 . We supposed whether decreased CD36 expression induced by UCHL1 is associated with UPS.…”

“…CD36, one of scavenger receptor class B family, in addition to the major function in facilitating lipid uptake by macrophages, could bind some ligands, such as thrombospondin-1, oxLDL, apoptotic cells, and cell-derived microparticles 34 . The expression of macrophage CD36 is increased by inhibiting lysosomal and proteasome, suggesting the regulation of CD36 level associates with the ubiquitin pathway 20 .…”

“…Interestingly, posttranslational modifications, such as ubiquitination, phosphorylation, were regulators in the regulation of protein stability 19 . Some reports have demonstrated that ubiquitin proteasome system (UPS) involved in the degradation of CD36 20 . Deubiquitinases (DUBs), a series of mediator in UPS, remove ubiquitin chains from their targeted proteins to stabilize their expressions.…”

The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer

“…IRS-1, the critical molecule downstream of the insulin and the insulin-like growth factor 1 receptor 64 , can be ubiquitinated by the CUL7 E3 ligase, suggesting that such tumor-suppressive activity might be related to CUL7-mediated targeted degradation of IRS-1. Recently, Sun et al revealed that CD36 could negatively regulate insulin activation, indicating that CD36 interacted with IRS-1, thereby abrogating the binding between IRS-1 and CUL7, which would further increase IRS-1 stability and affect insulin signaling 65 and might ultimately result in tumor suppression. In addition, the level of the voltage-gated potassium channel Eag2, which promotes cell migration in medulloblastoma 66 , 67 , is dramatically decreased by CUL7 overexpression 68 , which might also suppress the progression of tumors.…”

Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma

“…TGFβ and PDGF have been reported to promote biglycan expression through AKT activation [ 54 ]. It is considered that biglycan expression is promoted by AKT activation even in diabetes showing hyperinsulinemia, which activates AKT [ 55 , 56 ]. On the other hand, biglycan expression is induced in tumor vascular endothelial cells by promoter demethylation [ 33 ].…”